IP Library › Granted Patent US 50,527
Granted Patent E1
US 50,527 · App. 18/109,726 · Granted Aug 12, 2025

Covalent inhibitors of KRAS G12C

Inventors: Pingda Ren (San Diego, CA); Yi Liu (San Diego, CA); Liansheng Li (San Diego, CA); Jun Feng (San Diego, CA); Tao Wu (Carlsbad, CA)
Assignee: Araxes Pharma LLC
C07D205/04C07D211/56C07D211/58C07D211/60C07D211/62C07D213/64C07D213/74C07D231/40C07D237/04C07D285/14C07D285/16C07D295/16C07D401/04C07D401/12C07D403/04C07D403/06C07D403/12C07D405/06C07D419/12C07D471/04C07D487/04C07D487/10G01N33/58
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Quick Facts
Patent No.
US 50,527
App. No.
18/109,726
Granted
Aug 12, 2025
Kind
E1
Abstract

Irreversible inhibitors of G12C mutant K-Ras protein are provided. Also disclosed are methods to modulate the activity of G12C mutant K-Ras protein and methods of treatment of disorders mediated by G12C mutant K-Ras protein.

Claims (61)

1. A method for treating a cancer mediated by a K-Ras G12C, H-Ras G12C or N-Ras G12C mutation, the method comprising administering an effective amount of a compound having the following structure (VI):

or a pharmaceutically acceptable salt, tautomer, stereoisomer, solvate, isotopically-labeled derivative or prodrug thereof, to a subject in need thereof, wherein:

A is CR 37b , N or NR 38a ;

B is CR 37c , N, NR 38b or S;

C is CR 37d , N, NR 38c or S;

G 3 and G 4 are each independently N or CR, wherein R is H, cyano, halo or C 1 -C 6 alkyl C 1 -C 6 alkyl;

L 1a is a bond, —NH—, alkylene or heteroalkylene;

L 2 is a bond or alkylene;

R 32a and R 32b are, at each occurrence, independently H, —OH, —NH 2 , —CO 2 H, cyano, cyanoalkyl, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, hydroxylalkyl, aminoalkyl, carboxylalkyl or aminocarbonyl; or R 32a and R 32b join to form a carbocyclic or heterocyclic ring; or R 32a is H, —OH, —NH 2 , —CO 2 H, cyano, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, hydroxylalkyl, aminoalkyl, carboxylalkyl or aminocarbonyl and R 32b joins with R 33b to form a carbocyclic or heterocyclic ring;

R 33a and R 33b are, at each occurrence, independently H, —OH, —NH 2 , —CO 2 H, cyano, cyanoalkyl, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, hydroxylalkyl, aminoalkyl, carboxylalkyl or aminocarbonyl; or R 33a and R 33b join to form a carbocyclic or heterocyclic ring; or R 33a is H, —OH, —NH 2 , —CO 2 H, cyano, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, hydroxylalkyl, aminoalkyl, carboxylalkyl or aminocarbonyl and R 33b joins with R 32b to form a carbocyclic or heterocyclic ring;

R 37a , R 37b , R 37c , R 37d and R 37e are each independently H, halo, oxo, hydroxyl, cyano, aminocarbonyl, formyl, C 1 -C 6 alkyl, C 1 -C 6 alkylsulfonyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 hydroxylalkyl, C 1 -C 6 alkoxyalkyl, C 1 -C 6 aminoalkyl, heterocyclyl or aryl -OH, fluoro, chloro, bromo, iodo, oxo, methyl, methoxy, heteroaryl or aryl;

R 38a , R 38b and R 38c are each independently H, C 1 -C 6 alkyl or aryl;

n 3 and n 4 are each independently 1, 2 or 3;

m is 0 or 1;

is a single or double bond such that all valences are satisfied; and

E is an electrophilic moiety capable of forming a covalent bond with the cysteine residue at position 12 of a K-Ras, H-Ras or N-Ras G12C mutant protein.

2. The method of claim 1 , wherein the compound has one of the following structures (VIa), (VIb), (VIc), (VId), (VIe), (VIf) or (VIg):

3. The method of claim 1 , wherein the compound has one of the following structures (VIa′), (VIb′), (VIc′), (VId′), (VIe′), (VIf′) or (VIg′):

wherein:

Q is C(═O)—, NR 34 C(═O)—, —S(═O) 2 — or —NR 34 S(═O) 2 —;

R 34 is H, C 1 -C 6 alkyl or hydroxylalkyl;

is a carbon-carbon double bond or a carbon-carbon triple bond; and

R 35 and R 36 are each independently H, cyano, C 1 -C 6 alkyl, aminoalkyl, alkylaminoalkyl, or hydroxylalkyl or R 35 and R 36 join to form a carbocyclic or heterocyclic ring when is a double bond; or R 35 is absent and R 36 is H, C 1 -C 6 alkyl, aminoalkyl, alkylaminoalkyl or hydroxylalkyl when is a triple bond.

4. The method of claim 1 , wherein G 3 is N and G 4 is CR.

5. The method of claim 1 , wherein G 3 is CR and G 4 is N.

6. The method of claim 1 , wherein G 3 is N and G 4 is N.

7. The method of claim 1 , wherein n 3 is 2 and n 4 is 2.

8. The method of claim 1 , wherein n 3 is 1 and n 4 is 1.

9. The method of claim 1 , wherein n 3 is 2 and n is 1.

10. The method of claim 1 , wherein R 37a , R 37b , R 37c , R 37d and R 37e are each independently H, —OH, halo, oxo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, heterocyclyl or aryl.

11. The method of claim 10 , wherein R 37a , R 37b , R 37c , R 37d and R 37e are each independently H, —OH, fluoro, chloro, bromo, iodo, oxo, methyl, methoxy, heteroaryl or aryl.

12. The method of claim 1 , wherein R 37a or R 37e is aryl.

13. The method of claim 12 , wherein aryl is phenyl.

14. The method of claim 12 , where the aryl is substituted with one or more halo substituents.

15. The method of claim 14 , wherein the halo substituents are selected from fluoro and chloro.

16. The method of claim 1 , wherein R 37a is heteroaryl.

17. The method of claim 16 , wherein the heteroaryl is thiophenyl.

18. The method of claim 1 , wherein R 37a or R 37e , or both, is fluoro, chloro, bromo or iodo.

19. The method of claim 18 , wherein halo is chloro, bromo or iodo.

20. The method of claim 1 , wherein R 37a or R 37e has one of the following structures:

21. The method of claim 1 , wherein R 38a , R 38b and R 38c are each independently H or aryl.

22. The method of claim 21 , wherein R 38a , R 38b and R 38c are each independently H.

23. The method of claim 1 , wherein R 38c is aryl.

24. The method of claim 23 , wherein the aryl is substituted with one or more halo substituents.

25. The method of claim 24 , wherein halo is chloro.

26. The method of claim 3 , wherein Q is —C(═O)—.

27. The method of claim 3 , wherein each of R 35 and R 36 are H.

28. The method of claim 1 , wherein E has one of the following structures:

29. The method of claim 1 , wherein L 1a is a bond.

30. The method of claim 1 , wherein L 2 is a bond.

31. The method of claim 1 , wherein at least one of R 32a , R 32b , R 33a , or R 33b is H.

32. The method of claim 1 , wherein each of R 32a , R 32b , R 33a or R 33b is H.

33. The method of claim 1 , wherein the compound has one of the following structures:

34. The method of claim 1 , wherein the compound is formulated in a pharmaceutical composition comprising the compound and a pharmaceutically acceptable carrier.

35. The method of claim 34 , wherein the pharmaceutical composition is formulated for oral administration.

36. The method of claim 34 , wherein the pharmaceutical composition is formulated for injection.

37. The method of claim 1 , further comprising administering an additional anticancer agent to the subject.

38. The method of claim 1 , wherein the cancer is a hematological cancer, pancreatic cancer, MYH associated polyposis, colorectal cancer or lung cancer.

39. The method of claim 1 , wherein the compound has the following structure:

40. The method of claim 39 , wherein R 32a , R 32b , R 33a and R 33b are, at each occurrence, independently H, cyano, hydroxyalkyl or C 1 -C 6 alkyl.

41. The method of claim 39 , wherein R 32a , R 32b , R 33a and R 33b are, at each occurrence, independently H, cyano, -CH 2 OH or -CH 3 .

Continuity (6)
Division 15891304 · Feb 7, 2018
Division 14933734 · Nov 5, 2015
Division 14212656 · Mar 14, 2014
Provisional Application 61889480 · Oct 10, 2013
Provisional Application 61852123 · Mar 15, 2013
Reissue 16355258 · Mar 15, 2019
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